Volume 34, No 1, Jan 2024

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 34 Issue 1, January 2024: 58-75

ORIGINAL ARTICLES

ZNF689 deficiency promotes intratumor heterogeneity and immunotherapy resistance in triple-negative breast cancer

Li-Ping Ge^1,2,3,† , Xi Jin^1,2,† , Ding Ma^1,2,† , Zi-Yu Wang^1,2,† , Cheng-Lin Liu^1,2 , Chao-Zheng Zhou^1,2 , Shen Zhao^1,2 , Tian-Jian Yu^1,2 , Xi-Yu Liu^1,2 , Gen-Hong Di^1,2,* , Zhi-Ming Shao^1,2,3,* , Yi-Zhou Jiang^1,2,*

¹Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, China
²Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
³Human Phenome Institute, Fudan University, Shanghai, China
^†These authors contributed equally: Li-Ping Ge, Xi Jin, Ding Ma, Zi-Yu Wang
Correspondence: Gen-Hong Di(genhongdi@163.com)Zhi-Ming Shao(zhimingshao@fudan.edu.cn)Yi-Zhou Jiang(yizhoujiang@fudan.edu.cn)

Triple-negative breast cancer (TNBC) is an aggressive disease characterized by remarkable intratumor heterogeneity (ITH), which poses therapeutic challenges. However, the clinical relevance and key determinant of ITH in TNBC are poorly understood. Here, we comprehensively characterized ITH levels using multi-omics data across our center’s cohort (n = 260), The Cancer Genome Atlas cohort (n = 134), and four immunotherapy-treated cohorts (n = 109). Our results revealed that high ITH was associated with poor patient survival and immunotherapy resistance. Importantly, we identified zinc finger protein 689 (ZNF689) deficiency as a crucial determinant of ITH formation. Mechanistically, the ZNF689–TRIM28 complex was found to directly bind to the promoter of long interspersed element-1 (LINE-1), inducing H3K9me3-mediated transcriptional silencing. ZNF689 deficiency reactivated LINE-1 retrotransposition to exacerbate genomic instability, which fostered ITH. Single-cell RNA sequencing, spatially resolved transcriptomics and flow cytometry analysis confirmed that ZNF689 deficiency-induced ITH inhibited antigen presentation and T-cell activation, conferring immunotherapy resistance. Pharmacological inhibition of LINE-1 significantly reduced ITH, enhanced antitumor immunity, and eventually sensitized ZNF689-deficient tumors to immunotherapy in vivo. Consistently, ZNF689 expression positively correlated with favorable prognosis and immunotherapy response in clinical samples. Altogether, our study uncovers a previously unrecognized mechanism underlying ZNF689 deficiency-induced ITH and suggests LINE-1 inhibition combined with immunotherapy as a novel treatment strategy for TNBC.

https://doi.org/10.1038/s41422-023-00909-w

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